Contribution of Optical Genome Mapping (OGM) in the Diagnosis of Multiple Congenital Malformations With or Without Intellectual Disability Without Genetic Abnormality (CARTOGEN-N)

CARTOGEN-N_Contribution of Optical Genome Mapping (OGM) in the Diagnosis of Multiple Congenital Malformations With or Without Intellectual Disability Without Genetic Abnormality Detected by Whole Genome Sequencing

Congenital malformations result from an embryonic or foetal developmental disorder (DD) affecting one or more systems (cardiac, skeletal, nervous, etc.). These are referred to as multiple congenital anomalies (MCAs). They may be associated with an intellectual disability (ID)1.

Chromosomal analysis on Chromosomal Microarray Analysis (CMA) and gene panels or exome sequencing are the respective gold standard methods for chromosomal and molecular diagnosis of DD respectively2. In cases where no diagnosis is established after these first-line tests, short-read whole genome sequencing (WGS), via the Plan France Medicine Genomic 2020-2025 (AURAGEN), may be considered. This approach allows for diagnosis in nearly 40% of patients with DD3,4. However, many patients remain in diagnostic deadlock, likely due to the technical limitations of these methods, which potentially be overcome by emerging methodologies such as optical genome mapping (OGM)5,6,7,8,9. The investigators propose to systematically perform OGM in 30 patients presenting with MCA+/-ID who have inconclusive WGS result10.

The main objective is to assess the contribution of OGM in identifying structural variants not detected or poorly characterised by WGS in this clinical context. This work will also contribute to the ongoing of OGM in routine diagnostics and determine its role in the overall genetic diagnosis of MCA+/-ID. Additionally it may lead to the identification of new candidate genes and/or mechanisms of pathogenicity. If the results are promising, further clinical could expand this preliminary work into a larger-scale project. Improving the genetic diagnosis of DD should enhance the medical management of patients, currently in diagnostic deadlock, and their families.

Study Overview

• Status: Recruiting
• Conditions: Congenital Malformations
• Intervention / Treatment: Genetic: blood sample

Detailed Description

Study Workflow

Pre-analytical Phase

Participation in the study will be offered to all patients meeting the inclusion and non-inclusion criteria by an investigator from the Department of Genetics, during a medical consultation in which the non-contributive whole-genome sequencing (WGS) result will have been communicated (Figure 1). Information regarding the study procedures and objectives will be provided at that time. The information sheet and consent form will be given to the patient (if an adult) or to the holders of parental authority (if the patient is a minor). After obtaining consent for both the genetic investigations and participation in the research project, the patient may be enrolled in the study. Blood samples required for the study will be collected, transferred to the laboratory, and secured for analysis according to the following protocol:

Patient > 20 kg:

2 × 5 mL EDTA blood tubes

1. × 5 mL heparinized blood tube

   Patient 12-20 kg:

2. × 5 mL EDTA blood tubes

Patient 5-12 kg:

1 × 5 mL EDTA blood tube

Samples will be sent to the Cytogenetics Department, where they will be pseudonymized and secured. At least three aliquots of 1.5 mL EDTA blood and the remaining volume will be frozen at -80 °C for DNA extraction and long-fragment DNA extraction. A cell culture (peripheral blood lymphocytes) will also be performed to obtain a fixed chromosomal pellet from the heparinized tube, when available. If the heparinized sample is not available and the results of optical genome mapping require confirmation of a chromosomal abnormality by karyotype or FISH (i.e., contributive result), a second blood draw will be proposed during the clinical results-return consultation.

Analysis Frozen samples from the Cytogenetics Department of Clermont-Ferrand University Hospital (one per patient) will be transferred via TSE to the Department of Genetics at Reims University Hospital, designated to perform optical genome mapping while awaiting installation of the Saphyr scanner at Clermont-Ferrand University Hospital (DAN 2025 application).

Extraction, labeling, and imaging of long DNA molecules will be performed using the manufacturer's kits, following the provided instructions.

Results and Interpretation

Raw data will be analyzed and validated by cytogeneticists at Reims University Hospital using Bionano Access and Solve® software. Data will also be securely shared with the project lead, responsible for:

Performing a second independent analysis (with Bionano Access and Solve, available in the Cytogenetics Department), leveraging expertise acquired through participation in previous projects.

Providing final interpretation of results and disseminating clinically relevant findings for patient management.

Each sample will therefore benefit from dual review and dual expertise, ensuring the reliability of the results.

Parental segregation studies may be proposed to facilitate biological interpretation. If needed, collection of parental samples and consent procedures will be coordinated by the Department of Medical Genetics at Clermont-Ferrand University Hospital. Conclusive results will be communicated to the clinician who prescribed the WGS for patient management and genetic counselling.

• Study Type: Interventional
• Enrollment (Estimated): 55
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: LISE LACLAUTRE; Phone Number: +33473754963; Email: promo_interne_drci@chu-clermontferrand.fr

Study Locations

• France
  • Clermont-Ferrand, France
    • Recruiting
    • CHU Clermont-Ferrand
    • Contact: LISE LACLAUTRE; Phone Number: +33473754963; Email: promo_interne_drci@chu-clermontferrand.fr
    • Principal Investigator: Céline PEBREL-RICHARD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Patients presenting with at least two congenital anomalies, with or without intellectual disability, and weighing more than 5 kg.
• Whole-genome sequencing performed by the AURAGEN laboratory deemed non-contributive (absence of class 4 or 5 variants, or identification of a VUS, or identification of only one variant in the context of a recessive disorder).
• Patient covered by a social security scheme.
• Patient able to understand and to oppose participation in the study.
• Written informed consent for genetic analyses, signed either by the patient or by their legal representatives (for minors), after clear and fair information about the study has been provided.

Non-Inclusion Criteria

• Patients for whom a non-genetic cause (infectious, environmental, or toxic) has been previously identified.
• Inability to obtain a compliant sample.
• Patient or holder of parental authority under guardianship or legal protection, deprived of liberty, or placed under court-ordered protection.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: single arm of patients with congenital malformations	Genetic: blood sample; A blood sample will be collected after obtaining consent from the patient and/or their legal guardians. The number of tubes required (1 to 3) will be determined according to the patient's weight, for the purpose of performing optical genome mapping and any necessary confirmatory analyses in the event that a structural variant is identified.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
diagnostic yield of optical genome mapping (OGM) in multiple congenital anomalies with or without intellectual disability when whole-genome sequencing (WGS) is non-contributive	Assessing the diagnostic yield of optical genome mapping (OGM) in multiple congenital anomalies with or without intellectual disability when whole-genome sequencing (WGS) is non-contributive (absence of causal genetic variation or detection of a variant of uncertain significance (VUS) or a single variant in a recessive disorder).	day 1 (inclusion and blood collection)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of reclassified variants intially considered as VUS (Variants of Uncertain/Unknown Signification)	Assessment of the number of variants initially classified as VUS (variants of uncertain/unknown significance) that were reclassified as benign or pathogenic variants	day 1 (inclusion and blood collection)
Number of patients in whom a new candidate gene/pathogenic mechanism is identified		day 1 (inclusion and blood collection)
Evaluation of the feasibility (duration) of the technique in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria	Evaluation of technical duration (hours)	day 1 (inclusion and blood collection)
Evaluation of the feasibility of the technique (failure) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria	failure rate number	day 1 (inclusion and blood collection)
Evaluation of the feasibility of the technique (reprocessing) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria	reprocessing rate number	day 1 (inclusion and blood collection)
Evaluation of the feasibility of the technique (interpretation) in current practice in 1st-line, 2nd-line (after routine tests such as chromosomal microarray, exome sequencing…), or 3rd-line in the case of non-contributive WGS based on several criteria	Evaluation of biological interpretation time (hours)	day 1 (inclusion and blood collection)
Assess the impact of using these new technologies on patient management.	Percentage of patients for whom the OGM results led to a change in clinical management.	day 1 (inclusion and blood collection)

Collaborators and Investigators

• Sponsor: Céline PEBREL-RICHARD
• Investigators: Study Chair: Lise Laclautre, University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2025
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: December 9, 2025
• First Submitted That Met QC Criteria: January 20, 2026
• First Posted (Actual): January 27, 2026

Study Record Updates

• Last Update Posted (Actual): January 27, 2026
• Last Update Submitted That Met QC Criteria: January 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: genetic diagnosis; multiple congenital anomalies; structural variants; non-contributive whole-genome sequencing; optical genome mapping
• Additional Relevant MeSH Terms: Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Congenital Abnormalities; Abnormalities, Multiple; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: AOI 2024 PEBREL-RICHARD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No